Clinical Outcomes of Patients with Atrial Fibrillation who Survived from Bleeding Event: The Results from COOL-AF Thailand Registry.

BACKGROUND: Bleeding events are often reported among patients with atrial fibrillation (AF), irrespective of antithrombotic use. This study is to determine clinical outcomes of patients with AF who survived from bleeding event. METHODS: We analyzed data from COOL-AF (Cohort of Antithrombotic Use and Optimal International Normalized Ratio Levels in Patients with Atrial Fibrillation) Thailand registry. Outcomes of patients who experienced any bleeding were compared with patients who had never bleed. Time updated multivariate Cox-proportional hazard models were used to estimate the risk for clinical outcomes of patients with and without bleeding. RESULTS: Of total 3,405 patients (mean age: 67.8 ± 11.3 years; 41.9% female) in COOL-AF registry, 609 patients (17.9%) reported bleeding event occurs and 568 patients (93.3%) survived though hospital discharge. Patients who survived major bleeding (n = 126) were at increased risk for both death (adjusted hazard ratio [HR]: 4.44, 95% confidence interval [CI]: 2.91-6.75, p < 0.001) and stroke/systemic embolism (adjusted HR: 4.49, 95% CI: 2.19-9.24, p < 0.001). Minor bleeding also increased subsequent death (adjusted HR: 2.13, 95% CI: 1.56-2.90, p < 0.001). Up to 30% of patients who survived major bleeding and 6.3% of minor bleedings discontinued oral anticoagulation. Discontinuation was associated with very high death rate (42.1%), whereas patients who resumed oral anticoagulation after bleeding had lower mortality (10%). The most common causes of death in patients who survived a bleeding event were not related to cardiovascular causes nor bleeding. CONCLUSION: Patients with AF who have bleeding events have an increased risk for subsequent death and stroke and systemic embolism. These patients should be identified as vulnerable clinically complex patients and require a holistic approach to their AF management.

Increased small extracellular vesicle levels and decreased miR-126 levels associated with atrial fibrillation and coexisting diabetes mellitus.

BACKGROUND: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. Diabetes mellitus (DM) is one of the risk factors for the development of stroke and thromboembolism in patients with AF. Early identification may reduce the incidence of complications and mortality in AF patients. HYPOTHESIS: AF patients with DM have different pattern of small extracellular vesicle (sEV) levels and sEV-derived microRNA (miRNA) expression compared with those without DM. METHODS: We compared sEV levels and sEV-miRNA expression in plasma from AF patients with and without DM using nanoparticle tracking analysis and droplet digital polymerase chain reaction, respectively. RESULTS: We observed a significant increase in total sEV levels (p = .004) and a significant decrease in sEV-miR-126 level (p = .004) in AF patients with DM. Multivariate logistic regression analysis revealed a positive association between total sEV levels and AF with DM (p = .019), and a negative association between sEV-miR-126 level and AF with DM (p = .031). The combination of clinical data, total sEVs, and sEV-miR-126 level had an area under the curve of 0.968 (p < .0001) for discriminating AF with DM, which was shown to be significantly better than clinical data analysis alone (p = .0368). CONCLUSIONS: These results suggest that an increased level of total sEV and a decreased sEV-miR-126 level may play a potential role in the pathophysiology and complications of AF with DM, especially endothelial dysfunction, and can be considered as an applied biomarker for distinguishing between AF with and without DM.

Three-year outcomes of patients with non-valvular atrial fibrillation: the COOL-AF registry.

BACKGROUND: Clinical outcomes of patients with non-valvular atrial fibrillation (AF) in Asian populations may be different from non-Asians. In this study, we aimed to determine the incidence of ischemic stroke/systemic embolism (SSE), major bleeding, and death, and the predictors for clinical outcomes in a contemporary Asian cohort of newly diagnosed AF patients. METHODS: This is a prospective multicenter nationwide registry of patients with AF from 27 hospitals in Thailand. Baseline data and follow-up data were collected every 6 months until 3 years. Data collections included demographic, medical history, laboratory, and medication details. Clinical outcomes were SSE, major bleeding, and all-cause mortality. Incidence rates for each clinical outcome were calculated and presented as rate per 100 person-years. Univariate and multivariate analysis was performed to determine the independent predictors for clinical outcomes. RESULTS: There was a total of 3405 patients: mean age was 67.8 ± 11.3 years, 1981 (58.2%) were male. During 30.8 ± 9.7 months follow-up, there was a total of 132 SSE (3.9%), 191 major bleeding (5.6%), and 357 all-cause deaths (10.5%). The incidence rates of SSE, major bleeding, and death were 1.56 (1.30-1.84), 2.26 (1.96-2.61), and 4.17 (3.33-4.25), per 100 person-years respectively. Independent predictors for clinical outcomes were age, type of AF, and the presence of comorbid conditions. CONCLUSION: The incidence rate of SSE, major bleeding, and death remains high reflecting the unmet needs in AF management.

Increased expression of six-large extracellular vesicle-derived miRNAs signature for nonvalvular atrial fibrillation.

BACKGROUNDS: Non-valvular atrial fibrillation (AF) is the most common type of cardiac arrhythmia. AF is caused by electrophysiological abnormalities and alteration of atrial tissues, which leads to the generation of abnormal electrical impulses. Extracellular vesicles (EVs) are membrane-bound vesicles released by all cell types. Large EVs (lEVs) are secreted by the outward budding of the plasma membrane during cell activation or cell stress. lEVs are thought to act as vehicles for miRNAs to modulate cardiovascular function, and to be involved in the pathophysiology of cardiovascular diseases (CVDs), including AF. This study identified lEV-miRNAs that were differentially expressed between AF patients and non-AF controls. METHODS: lEVs were isolated by differential centrifugation and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), flow cytometry and Western blot analysis. For the discovery phase, 12 AF patients and 12 non-AF controls were enrolled to determine lEV-miRNA profile using quantitative reverse transcription polymerase chain reaction array. The candidate miRNAs were confirmed their expression in a validation cohort using droplet digital PCR (30 AF, 30 controls). Bioinformatics analysis was used to predict their target genes and functional pathways. RESULTS: TEM, NTA and flow cytometry demonstrated that lEVs presented as cup shape vesicles with a size ranging from 100 to 1000 nm. AF patients had significantly higher levels of lEVs at the size of 101-200 nm than non-AF controls. Western blot analysis was used to confirm EV markers and showed the high level of cardiomyocyte expression (Caveolin-3) in lEVs from AF patients. Nineteen miRNAs were significantly higher (> twofold, p < 0.05) in AF patients compared to non-AF controls. Six highly expressed miRNAs (miR-106b-3p, miR-590-5p, miR-339-3p, miR-378-3p, miR-328-3p, and miR-532-3p) were selected to confirm their expression. Logistic regression analysis showed that increases in the levels of these 6 highly expressed miRNAs associated with AF. The possible functional roles of these lEV-miRNAs may involve in arrhythmogenesis, cell apoptosis, cell proliferation, oxygen hemostasis, and structural remodeling in AF. CONCLUSION: Increased expression of six lEV-miRNAs reflects the pathophysiology of AF that may provide fundamental knowledge to develop the novel biomarkers for diagnosis or monitoring the patients with the high risk of AF.

Outcomes of patients with atrial fibrillation with and without diabetes: A propensity score matching of the COOL-AF registry.

BACKGROUND: To investigate the clinical outcomes of patients with non-valvular atrial fibrillation (NVAF) compared between those with and without diabetes mellitus (DM). METHODS: We conducted a prospective multicenter nationwide registry for patients with NVAF from 27 hospitals in Thailand. Patients were followed-up every 6 months until 3 years. The outcome measurements were ischemic stroke (IS) or transient ischemic attack (TIA), major bleeding, and heart failure (HF). All reported events were confirmed by the adjudication committee. DM was diagnosed by history or laboratory data. RESULTS: We studied 3402 patients. DM was diagnosed in 923 patients (27.1%). The average follow-up duration was 25.74 ± 10.57 months (7912 persons-year). The rate of IS/TIA, major bleeding, and HF was 1.42, 2.11, and 3.03 per 100 person-years. Patients with DM had a significantly increased risk of IS/TIA, major bleeding, and HF. After adjusting for age, gender, comorbid conditions, and the use of oral anticoagulant (OAC) using propensity score matching, DM remained a significant predictor of ischemic stroke/TIA, major bleeding and HF with Hazard ratio and 95% confidence interval of 1.67 (1.02, 2.73), 1.65 (1.13, 2.40), and 1.87 (1.34, 2.59), respectively. The net clinical benefit of OAC was more pronounced in DM patients (0.88 events per 100 person-years) than in those without DM (-0.73 events per 100 person-years). CONCLUSIONS: DM increases the risk of adverse clinical outcomes in NVAF patients. The benefit of OAC outweighs the risk in DM patients.

Influence of gender on the clinical outcomes of Asian non-valvular atrial fibrillation patients: insights from the prospective multicentre COOL-AF registry.

OBJECTIVE: To determine the effect of gender on clinical outcomes of Asian non-valvular atrial fibrillation patients. DESIGN: This is a cohort study. SETTING: 27 university and regional hospitals in Thailand. PARTICIPANTS: Patients with non-valvular atrial fibrillation. PRIMARY AND SECONDARY OUTCOMES MEASURES: The clinical outcomes were ischaemic stroke/transient ischaemic attack (TIA), major bleeding, intracerebral haemorrhage (ICH), heart failure and death. Follow-up data were recorded every 6 months until 3 years. Differences in clinical outcomes between males and females were determined. Multivariate analysis was performed to assess the effect of gender on clinical outcomes. Survival analysis and log-rank test were performed to determine the time-dependent effect of clinical outcomes, and the difference between males and females. Effect of oral anticoagulant (OAC) on outcomes and net clinical benefit of OAC was assessed. The analysis was performed both for the whole dataset and propensity score matching with multiple imputation. RESULTS: A total of 3402 patients (mean age: 67.4±11.3 years; 58.2% male) were included. Average follow-up duration 25.7±10.6 months (7192.6 persons-year). Rate of ischaemic stroke/TIA, major bleeding, ICH, heart failure and death were 1.43 (1.17-1.74), 2.11 (1.79-2.48), 0.70 (0.52-0.92), 3.03 (2.64-3.46) and 3.77 (3.33-4.25) per 100 person-years. Females had increased risk for ischaemic stroke/TIA and heart failure and males had increased risk for major bleeding and ICH. Ischaemic stroke/TIA risk in females and major bleeding and ICH risk in males remained even after correction for age, comorbid conditions and anticoagulation treatment. OAC reduced the risk of ischaemic stroke/TIA in males and females, and markedly increased the risk of major bleeding and ICH in males. CONCLUSIONS: Females had a higher risk of ischaemic stroke/TIA and heart failure, and a lower risk of major bleeding and ICH compared with males. OAC reduced risk of ischaemic stroke/TIA in females, and markedly increased risk of major bleeding and ICH in males.

Characteristics and antithrombotic treatment patterns of patients with concomitant coronary artery disease and atrial fibrillation from Thailand's COOL-AF registry.

BACKGROUND: Concomitant coronary artery disease (CAD) and atrial fibrillation (AF) are common in clinical practice. The aim of this study was to investigate the characteristics and antithrombotic treatment patterns of patients with concomitant CAD and AF from the COhort of antithrombotic use and Optimal INR Level in patients with non-valvular atrial fibrillation in Thailand (COOL-AF Thailand) registry. METHODS: Registry enrollment criteria included patients aged ≥ 18 years who were diagnosed with AF for any duration at any of 27 public hospitals located across Thailand during 2014-2017. The That Clinical Trials Registry study registration number is TCTR20160113002. Statistical comparisons of characteristics and treatment strategies were performed between patients with and without CAD. RESULTS: Of a total of 3461 AF patients, 557 had concomitant CAD (16.1%). Patients with concomitant CAD and AF were significantly older, more likely to be male, had more comorbidities, and had more cardiovascular implantable electronic devices. History of stroke/transient ischemic attack and prior bleeding was not significantly different between groups. CHA2DS2-VASc score and HAS-BLED score were both higher in patients with CAD than in patients without CAD (4.17 vs. 2.78, p < 0.001, and 2.01 vs. 1.45, p < 0.001, respectively). Utilization of oral anticoagulant was less in patients with CAD (76.0% vs. 84.3%, p < 0.001). Concomitant use of antiplatelet was found to be a major cause of oral anticoagulant (OAC) underutilization. Specifically, the rate of OAC prescription was 95.9% in patients without antiplatelet, and 43.7% in patients with antiplatelet. Among patients with CAD who were on OAC, the rate of concomitant antiplatelet prescription was still high. In this group, 63% of patients were on triple therapy when percutaneous coronary intervention (PCI) with drug eluting stent was performed within 1 year, and 32.2% of patients without prior PCI or acute coronary syndrome were taking at least one antiplatelet with OAC. CONCLUSION: Among patients with concomitant CAD and AF, physicians were reluctant to discontinue antiplatelet. The use of antiplatelet discourages physicians from prescribing OAC. Underutilization of OAC may increase the risk of ischemic stroke, and an inappropriate combination of OAC and antiplatelet may increase the risk of bleeding. Trial registration The trial has been registered with the Thai Clinical Trials Registry (TCTR) which complied with WHO International Clinical Trials Registry Platform dataset. The Registration Number is TCTR20160113002 (05/01/2016).

Impact of anemia on clinical outcomes of patients with atrial fibrillation: The COOL-AF registry.

BACKGROUND: To determine whether anemia is an independent risk factor for ischemic stroke and major bleeding in patients with non-valvular atrial fibrillation (NVAF). HYPOTHESIS: Anemia in patients with NVAF increase risk of clinical complications related to atrial fibrillation. METHODS: We conducted a prospective multicenter registry of patients with NVAF in Thailand. Demographic data, medical history, comorbid conditions, laboratory data, and medications were collected and recorded, and patients were followed-up every 6 months. The outcome measurements were ischemic stroke or transient ischemic attack (TIA), major bleeding, heart failure (HF), and death. All events were adjudicated by the study team. We analyzed whether anemia is a risk factor for clinical outcomes with and without adjusting for confounders. RESULTS: There were a total of 1562 patients. The average age of subjects was 68.3 ± 11.5 years, and 57.7% were male. The mean hemoglobin level was 13.2 ± 1.8 g/dL. Anemia was demonstrated in 518 (33.16%) patients. The average follow-up duration was 25.8 ± 10.5 months. The rate of ischemic stroke/TIA, major bleeding, HF, and death was 2.9%, 4.9%, 1.8%, 8.6%, and 9.2%, respectively. Anemia significantly increased the risk of these outcomes with a hazard ratio of 2.2, 3.2, 2.9, 1.9, and 2.8, respectively. Oral anticoagulants (OAC) was prescribed in 74.8%; warfarin accounts for 89.9% of OAC. After adjusting for potential confounders, anemia remained a significant predictor of major bleeding, heart failure, and death, but not for ischemic stroke/TIA. CONCLUSION: Anemia was found to be an independent risk factor for major bleeding, heart failure, and death in patients with NVAF.